Primary Care of the Solid Organ Transplant Recipient

Primary Care of the Solid Organ

Transplant Recipient

FRANCESCA M. CIMINO, MD, Uniformed Services University of the Health Sciences, Bethesda, Maryland KATHERINE A.M. SNYDER, MD, Naval Hospital Bremerton, Bremerton, Washington

The advancing science of transplantation has led to more transplants and longer survival. As a result, primary care physicians are more involved in the care of transplant recipients. Immunosuppressive therapy has significantly decreased rates of transplant rejection but accounts for more than 50% of transplant-related deaths, often due to infections and other risks related to long-term use. Cardiovascular disease is the leading cause of non?transplantrelated mortality. Aggressive risk factor management is recommended for transplant recipients, including a blood pressure goal of less than 130/80 mm Hg and statin therapy in kidney, liver, and heart recipients. Fertility typically increases posttransplant, and female transplant recipients should avoid pregnancy for one year after surgery. The best contraceptive choice is usually an intrauterine device. Because of the increased risk of infection, patients should be tested for graft dysfunction or infection if suspicion arises. Testing should be coordinated with the transplant center. Malignancies are a common cause of death in transplant recipients, requiring careful attention to screening recommendations and informed discussions with patients. Family physicians should maintain an ongoing relationship with the transplant team to discuss medication changes and the risk of infection or graft rejection. (Am Fam Physician. 2016;93(3):203-210. Copyright ? 2016 American Academy of Family Physicians.)

CME This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions on page 176.

Author disclosure: No relevant financial affiliations.

Since 1988, more than 600,000 solid organ transplants have been performed in the United States, and approximately 130,000 patients are currently awaiting transplants.1 Five-year survival rates after liver and kidney transplants are 64% and 70%, respectively, and heart and lung recipients have a five-year survival rate of more than 50%.1 Because of the increasing number of surviving transplant recipients, care is gradually shifting to the primary care physician's office. This article focuses on the primary care of adults who have received solid organ transplants.

Medications

Immunosuppressive therapy accounts for more than 50% of transplant-related deaths, often due to infections and other risks related to long-term use.2 Patients typically receive high doses of two or more medications immediately after transplantation, with subsequent tapering over the following months to years to minimize long-term adverse effects.

Medication classes that reduce the risk of graft rejection include calcineurin inhibitors, which inhibit an enzyme that stimulates

T lymphocytes; mammalian target of rapamycin inhibitors, which impede cell growth and proliferation; and purine synthesis inhibitors, which include azathioprine (Imuran), methotrexate, and the commonly used subclass of mycophenolic acid derivatives, which inhibit enzymes needed for the growth of T and B lymphocytes. Corticosteroids are often also used early after transplantation, but are tapered as quickly as possible.3 Most of the preferred immunosuppressive medications are metabolized through the cytochrome P450 3A4 pathway and can interact with other medications. Because transplant recipients receive multiple medications, primary care physicians should be mindful of polypharmacy when starting new drugs. Table 1 reviews these medications, including adverse effects and examples of significant drug-drug interactions.4,5 Because of the extensive list of interactions, particularly with calcineurin inhibitors, changes to any medication should be discussed with the transplant team.

Posttransplant Disease Management

Cardiovascular disease and renal failure are the leading causes of posttransplant morbidity and mortality independent of graft

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Transplant Care Table 1. Posttransplant Immunosuppressive Medications and Drug Interactions

Medication class

Common adverse effects

Substances that increase concentration (not fully inclusive)*

Substances that decrease concentration*

Calcineurin inhibitors (e.g., cyclosporine [Sandimmune], tacrolimus [Prograf])

Hyperkalemia, hypertension, nephrotoxicity, neurotoxicity (e.g., headaches, tremors, neuropathy, seizures)

Cyclosporine: dyslipidemia, gingival hyperplasia

Tacrolimus: diabetes mellitus

Aminoglycosides Amphotericin B Antifungals: fluconazole (Diflucan),

itraconazole (Sporanox), ketoconazole Cardiac medications: amiodarone Contraceptives: ethinyl estradiol Diuretics: spironolactone (hyperkalemia) Fluoroquinolones (primarily ofloxacin;

ciprofloxacin and levofloxacin [Levaquin] often used safely) Grapefruit and grapefruit juice Macrolides (erythromycin more than clarithromycin [Biaxin]) Metronidazole (Flagyl) Nondihydropyridine calcium channel blockers: diltiazem, verapamil Nonsteroidal anti-inflammatory drugs (can increase nephrotoxicity) Pineapple and papaya (inhibit cyclosporine metabolism) Pomegranates and pomegranate juice Warfarin (Coumadin)

Antacids Antibiotics: nafcillin, rifampin Anticonvulsants:

carbamazepine (Tegretol), phenytoin (Dilantin) Cholestyramine (Questran) Loperamide (Imodium) Supplements: echinacea (may cause organ rejection), St. John's wort Valproic acid (Depakene)

Mammalian target of rapamycin inhibitors (e.g., sirolimus, everolimus)

Dyslipidemia, hepatic artery thrombosis, myelosuppression, poor wound healing, pulmonary fibrosis, rash, ulcerations

Ciprofloxacin

Linezolid (Zyvox; increased myelosuppression)

Macrolides (erythromycin more than clarithromycin)

Rifampin

Purine synthesis inhibitors (e.g., azathioprine [Imuran], mycophenolate [Cellcept], mycophenolic acid [Myfortic])

Azathioprine: cholestatic hepatitis

Mycophenolate/mycophenolic acid: bone marrow suppression, gastrointestinal issues (e.g., abdominal pain, diarrhea, gastritis, nausea)

Linezolid

Valganciclovir (Valcyte; increased myelosuppression)

Allopurinol can increase levels to toxic levels (especially azathioprine)

Rifampin

*--All immunosuppressive medications listed are metabolized through the cytochrome P450 34A pathway; thus, medications that inhibit this pathway will increase circulating levels of those drugs, and those that induce that pathway will decrease levels.

Information from references 4 and 5.

rejection.4 Increased cardiovascular risk is thought to be mediated by increased rates of hypertension, diabetes mellitus, hyperlipidemia, and obesity. Table 2 summarizes risk factors and provides recommendations for screening and treatment of posttransplant systemic diseases.4-8

HYPERTENSION

The Eighth Joint National Committee did not specifically address the target blood pressure range for solid organ transplant recipients.9 The goal suggested by transplant experts is less than 130/80 mm Hg.4,6 The choice of antihypertensive therapy depends on patient comorbidities and the immunosuppressive regimen. There is only limited evidence supporting the use of specific

antihypertensive classes, and transplant experts do not strongly recommend any class for first-line therapy.

Calcium channel blockers (CCBs) may counteract the vasoconstrictive effects of calcineurin inhibitors to control blood pressure and reduce nephrotoxicity. A Cochrane review found 17 randomized trials comparing CCBs with placebo or no treatment in 1,255 patients.10 Based on low-quality evidence, it concluded that CCB use may reduce the risk of graft loss (68 vs. 90 per 1,000 over a median of one year) but has no effect on overall mortality or acute graft rejection. Dihydropyridine CCBs are less likely to interact with calcineurin inhibitors, and the Cochrane review concluded that they may have a more favorable effect on serum creatinine

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Table 2. Posttransplant Care of Metabolic Diseases

Transplant Care

Condition

Screening intervals

Treatment considerations*

Treatment goals*

Chronic kidney Annually (minimum): GFR and spot urine

Consider renal-sparing maintenance

--

disease

protein (or albumin)-to-creatinine ratio

immunosuppressives

Increase frequency in patients with rapid decline or GFR < 60 mL per minute per 1.73 m2

Diabetes mellitus

Kidney and liver recipients: every three months for first year, then annually; after substantially increasing dose of calcineurin inhibitor, mammalian target of rapamycin inhibitor, or cyclosporine (Sandimmune)

Oral hypoglycemics and insulin are safe

Kidney recipients: aspirin for primary prevention of cardiovascular disease

Kidney recipients: A1C < 7% to 7.5%

Liver recipients: A1C < 7%

Hyperlipidemia Kidney and heart recipients: not specified Liver recipients: annually

Statin doses are generally lower than in general population; 50% reduction when used with cyclosporine

Liver recipients: isolated triglycerides may be treated initially with fish oil (1 g two times daily to 4 g daily as tolerated)

Kidney recipients: triglycerides < 500 mg per dL (5.7 mmol per L)

Liver recipients: low-density lipoprotein < 100 mg per dL (2.59 mmol per L)

Hypertension Every appointment

Use caution with diltiazem and verapamil Kidney and liver recipients:

(drug interactions)

< 130/80 mm Hg

Osteopenia / osteoporosis

Heart recipients: one year after transplant; then annually if receiving corticosteroids or bisphosphonates; if osteopenic, repeat every two years; if normal, repeat every three years

Kidney recipients: measure calcium, PTH, phosphorus, and vitamin D levels at intervals determined by baseline values, level of pre-transplant disease, and renal function; GFR > 30 mL per minute per 1.73 m2, check bone mineral density three months posttransplant if receiving corticosteroids or if patient has osteoporosis risk factors

Liver: initially, then annually for first five years posttransplant; if osteopenic, every two to three years if normal

Kidney recipients: consider vitamin D, calcitriol (Rocaltrol), alfacalcidol, or bisphosphonates if GFR > 30 mL per minute per 1.73 m2 and low bone mineral density; manage abnormalities in calcium, phosphorus, vitamin D, and PTH levels as in the pretransplant population

Liver recipients: bisphosphonate treatment for patients with osteoporosis or osteopenia with other risk factors

Heart and liver recipients: serum 25-hydroxyvitamin D levels > 30 ng per mL (75 nmol per L)

GFR = glomerular filtration rate; PTH = parathyroid hormone. *--Treatment considerations and goals include specific recommendations if targets are different from the general population. Information from references 4 through 8.

levels and glomerular filtration rate.10 However, nondihydropyridine CCBs may be used if therapeutic levels of calcineurin inhibitors are monitored.4,6,10 Use of a nondihydropyridine CCB can reduce dosage requirements and therefore the cost of calcineurin inhibitors.6,7 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are first-line agents in kidney recipients if urinary protein excretion exceeds 1 g per day, but their use can cause increased serum creatinine levels, hyperkalemia, and anemia.7 Thiazide diuretics are recommended in kidney recipients to counteract the sodium-related effects of calcineurin inhibitors. However, loop and thiazide diuretics should be used with caution in liver recipients.4,7 Kidney recipients with resistant

hypertension should be referred back to the transplant center to rule out allograft vascular compromise and complications related to the native kidneys, which are not typically removed during transplant surgery.7

HYPERLIPIDEMIA

Statins are the preferred agent to treat hyperlipidemia and reduce cardiovascular risk in solid organ transplant recipients. The American Association for the Study of Liver Disease/American Society of Transplantation recommends a low-density lipoprotein goal of less than 100 mg per dL (2.59 mmol per L) in liver recipients.4 The Kidney Disease Improving Global Outcomes and International Society of Heart and Lung

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Transplant Care

Table 3. Tests to Monitor for Transplant Rejection

Transplantation guidelines recommend universal statin therapy in kidney and heart recipients.5,8 Initial statin doses in all solid organ transplant recipients are lower than those in the general population because of potential interactions with calcineurin inhibitors.5,8

All of the recommendations above are based on expert opinion. A 2014 Cochrane review of 22 studies with 3,465 patients found that statin therapy had inconsistent or uncertain effects on all-cause and cardiovascular mortality, major cardiovascular events, and fatal or nonfatal myocardial infarctions in kidney recipients.11 Evidence favoring statin treatment is more robust in heart recipients; statin therapy in first-time recipients reduces rates of mortality and allograft rejection with hemodynamic compromise at one year,12 reduces cardiac allograft vasculopathy, and improves long-term outcomes regardless of lipid levels.5

CHRONIC KIDNEY DISEASE

Non-kidney solid organ transplant recipients have higher posttransplant rates of chronic kidney disease. Strategies recommended to reduce disease progression mirror those in the general population: blood pressure and glucose control, and use of medications that block the renin-angiotensin-aldosterone system. Additionally, transplant centers may decrease calcineurin inhibitor doses, potentially transitioning to an inhibitor-free regimen to preserve renal function.4,5

DIABETES

Diabetes can be preexisting or can occur for the first time posttransplant. All major transplant societies recommend screening and treatment, in accordance with guidelines from the American Diabetes Association.4,5,7 The target A1C is less than 7% in most transplant recipients.4,5,7 Insulin is typically required, but oral hypoglycemic agents can also be used with the same restrictions for comorbid conditions as in the general population.4,7 The use of thiazolidinediones has not been proven safe in liver recipients.4 The risk of new-onset diabetes is highest in the first three months after transplantation. Although there is no consistent evidence that new-onset diabetes resolves as immunosuppressive therapy is tapered, glycemic control often improves with time.4,5,7

OBESITY

Obesity (body mass index greater than 30 kg per m2) occurs in roughly 20% to 30% of liver and kidney recipients who were not obese before the transplant.4,13 Improved appetite after transplantation and medication adverse effects are likely contributing factors.4 Lifestyle

Transplant type Typical graft function assessment

Heart Kidney

Liver Lung

Endomyocardial biopsy

Urine protein levels (total, protein-tocreatinine ratio, albumin-to-creatinine ratio), serum creatinine level (to calculate glomerular filtration rate)

Transaminase, bilirubin, and alkaline phosphatase levels

Bronchoscopy with transbronchial biopsies, pulmonary function testing

Information from references 4, 5, 7, and 18.

modifications remain the cornerstone of therapy, but bariatric surgery is not contraindicated.4,7

BONE DISEASE

Osteopenia and osteoporosis are common before transplantation. Multiple factors, including corticosteroid therapy, cause bone mineral density to decrease and fracture risk to increase in the immediate posttransplant period.14,15 Although transplant experts use standard definitions for osteoporosis and osteopenia based on bone mineral density, fracture risk in solid organ transplant recipients does not correlate directly with these values.5,15,16

Evidence regarding fracture risk reduction with any agent is inconsistent.15,17 Kidney recipients can have abnormal serum levels of phosphorus, parathyroid hormone, and vitamin D. Treatment for these conditions should be similar to that in the pretransplant period. In kidney recipients with osteoporosis, bisphosphonate therapy is recommended only in the first year after the transplant. Bone biopsy should be considered in kidney recipients because of their increased risk of adynamic bone disease, which is worsened by bisphosphonate use.15 Heart recipients should receive bisphosphonates for the first year after transplant to prevent bone loss.5 Bisphosphonate therapy is also recommended for liver recipients who have osteoporosis or osteopenia with risk factors.4

Graft Dysfunction

Graft dysfunction is often first noted through routine screening tests or surveillance biopsies. Screening for rejection or other graft complications is site-specific and based on individual patient characteristics, including time from transplant and stability of previous testing.4 The transplant team should be notified immediately if there is any concern for graft dysfunction or rejection. Table 3 presents typical screening tests according to transplant type.4,5,7,18

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Table 4. Comparison of Contraceptives for Transplant Recipients

Transplant Care

Contraceptive

Advantages

Disadvantages

Combined oral contraceptives

Intrauterine devices

Intravaginal ring and combined hormonal contraceptive patch

Medroxyprogesterone (Provera)

Subdermal implants

Widely available and affordable

No increased risk of infection; no change in effectiveness for immunosuppressed patients; no drug interactions; does not contain estrogen

Avoids first-pass effect; may decrease risk of drug interactions with estrogen; intravaginal ring has lower total daily dose of estrogen

Avoids first-pass effect; does not contain estrogen

Fewer bone density effects compared with medroxyprogesterone; does not contain estrogen

Failure rate for typical use is 8%; estrogen-containing contraceptives may increase blood levels of corticosteroids, cyclosporine (Sandimmune), tacrolimus (Prograf), and sirolimus

--

Complications related to estrogen-containing contraceptives; increased circulating levels of estrogen with patch

U.S. Food and Drug Administration boxed warning for bone health combined with propensity for decreased bone mineral density

--

Information from references 19 through 21.

Reproductive and Sexual Health

Transplant recipients often struggle with infertility, erectile dysfunction, and other reproductive and sexual concerns before and after the transplant. Fertility generally improves post-transplant.19,20 The National Transplantation Pregnancy Registry follows pregnancy outcomes, and patients are encouraged to register; enrollment forms are available at ofl .

Male transplant recipients often have incomplete recovery of gonadal function, but are still able to father a child. Erectile dysfunction can be treated with phosphodiesterase-5 inhibitors.4,5,7 The risk of pregnancy complications is not increased when the father is a kidney recipient. Men may wish to bank sperm before they use mammalian target of rapamycin inhibitors.7

Pregnancy during the 12 months following trans plantation is associated with an increased risk of preterm delivery and graft dysfunction, rejection, or loss.19,21 Reliable contraception should be used before the transplant because ovulation can occur as early as one month posttransplant. The use of an intrauterine device avoids interactions with medications, does not increase the risk of infection, and is not affected by typical immunosuppressive therapies. For these reasons, physicians should encourage female transplant recipients to strongly consider an intrauterine device for contraception.20,21 The medical eligibility criteria for contraceptive use from the Centers for Disease Control and Prevention include specific recommendations for contraceptive types during the first two years after solid organ transplantation.22 A comparison of contraceptive methods specific to transplant recipients is presented in Table 4.19-21

Transplant centers should be notified before attempts to conceive; this allows for evaluation of

graft function and adjustment of immunosuppressive regimens, if needed. Ideally, patients should not have experienced graft rejection within the past year; should have stable graft function, no acute infections, and controlled comorbidities; and should be on a stable immunosuppressive regimen before conceiving.4,7,19 Certain immunosuppressive agents should be discontinued before pregnancy because of the increased risk of fetal compromise. Mycophenolic acid compounds have about a 25% risk of birth defects, and mammalian target of rapamycin inhibitors increase the risk of preterm delivery, decreased fetal weight, and delayed skeletal ossification.7,19,23 Azathioprine, cyclosporine (Sandimmune), and tacrolimus (Prograf) have not been shown to increase the risk of birth defects.19

Transplant recipients have a high risk of miscarriage, gestational hypertension, preeclampsia, gestational diabetes, and fetal complications such as prematurity and low birth weight. They typically require consultation or management by obstetricians and maternal-fetal medicine subspecialists. Although cesarean deliveries are not routinely recommended, they are performed more often in kidney (44%) and liver (57%) recipients.19

Most transplant recipients may safely breastfeed their infants. The benefits of breastfeeding while receiving corticosteroids, cyclosporine, tacrolimus, or azathioprine outweigh the risks of drug exposure. Physicians should monitor infant serum drug levels for the first few weeks of life, and should recommend discontinuing breastfeeding only if measurable levels are detected. Breastfeeding is not recommended for mothers receiving mycophenolic acid (Myfortic), sirolimus, everolimus, or belatacept (Nulojix); these agents have limited safety data, and mycophenolic acid is known to increase the risk of fetal malformations from in utero exposure.23

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